• Something wrong with this record ?

Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis

P. Drevinek, T. Pressler, M. Cipolli, K. De Boeck, C. Schwarz, F. Bouisset, M. Boff, N. Henig, N. Paquette-Lamontagne, S. Montgomery, J. Perquin, N. Tomkinson, W. den Hollander, JS. Elborn

. 2020 ; 19 (1) : 99-107. [pub] 20190607

Language English Country Netherlands

Document type Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21020824

Grant support
R35 HL135816 NHLBI NIH HHS - United States
U54 TR001005 NCATS NIH HHS - United States

BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21020824
003      
CZ-PrNML
005      
20210830102450.0
007      
ta
008      
210728s2020 ne f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.jcf.2019.05.014 $2 doi
035    __
$a (PubMed)31182369
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a ne
100    1_
$a Drevinek, Pavel $u Department of Medical Microbiology and Department of Paediatrics, Motol University Hospital and Second Faculty of Medicine, Charles University, V Uvalu, 84, Prague 15006, Czech Republic
245    10
$a Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis / $c P. Drevinek, T. Pressler, M. Cipolli, K. De Boeck, C. Schwarz, F. Bouisset, M. Boff, N. Henig, N. Paquette-Lamontagne, S. Montgomery, J. Perquin, N. Tomkinson, W. den Hollander, JS. Elborn
520    9_
$a BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.
650    _2
$a aplikace inhalační $7 D000280
650    _2
$a dospělí $7 D000328
650    _2
$a klinické křížové studie $7 D018592
650    12
$a cystická fibróza $x farmakoterapie $x genetika $x patofyziologie $7 D003550
650    _2
$a protein CFTR $x genetika $7 D019005
650    12
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a dvojitá slepá metoda $7 D004311
650    _2
$a monitorování léčiv $x metody $7 D016903
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a mutace $7 D009154
650    12
$a oligonukleotidy $x aplikace a dávkování $x škodlivé účinky $7 D009841
650    _2
$a antisense oligonukleotidy $x aplikace a dávkování $x škodlivé účinky $7 D016376
650    _2
$a respirační funkční testy $x metody $7 D012129
650    _2
$a určení symptomu $x metody $7 D063189
650    _2
$a výsledek terapie $7 D016896
655    _2
$a časopisecké články $7 D016428
655    _2
$a randomizované kontrolované studie $7 D016449
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Pressler, Tacjana $u Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen 02100, Denmark
700    1_
$a Cipolli, Marco $u Cystic Fibrosis Centre -Azienda, Ospedaliera Universitaria Integrata di Verona, P. le Stefani 1, Verona 37126, Italy; Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria di Ancona, via Conca 71, Ancona 60020, Italy
700    1_
$a De Boeck, Kris $u University Hospital of Leuven, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
700    1_
$a Schwarz, Carsten $u Charité Universitätsmedizin Berlin, Mittelallee 4, Augustenburger Platz 1, Berlin 13353, Germany
700    1_
$a Bouisset, Florilene $u Cytel, Route de Pre-Bois, 20, 1216 Geneva, Switzerland; GSK Consumer Health, Route de l'Etraz 2, 1260 Nyon, Switzerland
700    1_
$a Boff, Marie $u Cytel, Route de Pre-Bois, 20, 1216 Geneva, Switzerland
700    1_
$a Henig, Noreen $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands; Breath Therapeutics Inc., 633 Menlo Ave Ste 230, Menlo Park, CA, USA
700    1_
$a Paquette-Lamontagne, Nicolas $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands; Blueprint Medicines Corporation, 45 Sidney St., Cambridge, MA 02139, USA
700    1_
$a Montgomery, Sonya $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands; Gyroscope Therapeutics, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Herts SG1 2FX, UK
700    1_
$a Perquin, Jaakko $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands
700    1_
$a Tomkinson, Nigel $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands
700    1_
$a den Hollander, Wilhelmina $u ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands
700    1_
$a Elborn, J Stuart $u Faculty of Medicine, Health & Life Sciences, 90 Lisburn Road, Belfast BT9 6AG, Northern Ireland. Electronic address: s.elborn@qub.ac.uk
773    0_
$w MED00006892 $t Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society $x 1873-5010 $g Roč. 19, č. 1 (2020), s. 99-107
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31182369 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20210728 $b ABA008
991    __
$a 20210830102450 $b ABA008
999    __
$a ok $b bmc $g 1691415 $s 1141270
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 19 $c 1 $d 99-107 $e 20190607 $i 1873-5010 $m Journal of cystic fibrosis $n J Cyst Fibros $x MED00006892
GRA    __
$a R35 HL135816 $p NHLBI NIH HHS $2 United States
GRA    __
$a U54 TR001005 $p NCATS NIH HHS $2 United States
LZP    __
$a Pubmed-20210728
Back

Find record

Citation metrics

Archiving options